This application is a U. S. national phase entry, prudent to 35 USC 371, of PCT/EP00/04896, filed May 26, 2000 and published on Dec. 14, 2000, International Publication No. WO 00/75102, which claims the benefit of European Application No. 99500089.0 filed Jun. 3, 1999.
In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA) The receptors that respond to glutamate are called excitatory amine acid receptors (EAA receptors). See Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general. types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed xe2x80x9cionotropicxe2x80x9d. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D or C, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
The metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation. Compounds which modulate the function of these receptors, in particular agonists and antagonists of glutamate, are useful for the treatment of acute and chronic neurodegenerative conditions, and as antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant, and anti-emetic agents.
Pellicciari et al., J. Med. Chem., 1996, 39, 2259-2269 refers to compounds known as metabotropic glutamate receptor agonists, in particular (2S,1xe2x80x2S,2xe2x80x2S)-2-(2-carboxycyclopropyl)glycine, also known as L-CCG-I; (2S,1xe2x80x2S,2xe2x80x2R,3xe2x80x2R)-2-(2xe2x80x2-carboxy-3xe2x80x2-(methoxymethyl)cyclopropyl-glycine, also known as cis-MCG-I; (2S,1xe2x80x2S,2xe2x80x2R,3xe2x80x2S)-2-(2xe2x80x2-carboxy-3xe2x80x2-(methoxymethyl)cyclopropylglycine, also known as trans-MCG-I; and (2S,1xe2x80x2R,2xe2x80x2R,3xe2x80x2R)-2-(2xe2x80x2,3xe2x80x2-dicarboxycyclopropyl)glycine, also known as DCG-IV. The paper also describes the synthesis of the sixteen possible stereoisomers of 2-(2xe2x80x2-carboxy-3xe2x80x2-phenylcyclopropyl)glycine and their evaluation as excitatory amino acid receptor ligands. The compound (2S,1xe2x80x2S,2xe2x80x2S,3xe2x80x2R)-2-(2xe2x80x2-carboxy-3xe2x80x2-phenylcyclopropyl)glycine, also known as PCCG 4 is reported to be a metabotropic glutamate receptor antagonist.
Japanese patent application publication number JP 06179643 discloses MCG and generically discloses (2S,1xe2x80x2S,2xe2x80x2R)-2-(2-carboxy-3-alkoxymethyl- and 3-aralkoxymethyl-cyclopropyl)glycines as glutamate receptor agonists.
International patent application publication number WO 97/19049 discloses PCCG 4 and also generically discloses various 2-carboxy-3-arylcyclopropylglycines having affinity for metabotropic glutamate receptors.
International patent application publication number WO 98/00391 discloses 2-carboxy-3,3-dihalocyclopropylglycines, including (2S,1xe2x80x2S,2xe2x80x2S)-2-(2-carboxy-3,3-difluoro)-cyclopropylglycine as metabotropic glutamate receptor agonists.
European patent application, publication number EP-A1-0870760 discloses that certain 3-substituted 2-carboxycyclopropyl glycine derivatives are modulators of metabotropic glutamate receptor function. The preferred compounds are said to be those in which the substituents at the 1 and 2 positions are in a trans relationship. The examples illustrate such compounds in which the substituents at the 1 and 3 positions are also in a trans relationship. One such compound is (2S,1xe2x80x2S,2xe2x80x2S,3xe2x80x2S)-2xe2x80x2-carboxy-3xe2x80x2-methylcyclopropylglycine.
Surprisingly, novel 3-substituted 2-carboxycyclopropyl glycine derivatives having the substituents at the 1 and 2 positions in a trans relationship, and those at the 1 and 3 positions in a cis relationship, have now been found which are potent agonists of glutamate at metabotropic glutamate receptors.
Accordingly, the present invention provides a compound of the formula: 
in which R1 is C1-10 alkyl; C2-10 alkenyl; C2-10 alkynyl; phenyl-C2-10 alkyl or phenyl-C2-10 alkenyl; or a salt or ester thereof.
Compounds of the invention have been found to be agonists of glutamate at metabotropic glutamate receptors and are therefore useful in the treatment of disorders of the central nervous system such as neurological diseases, for example neurodegenerative diseases, and as antipsychotic, anxiolytic, drug-withdrawal, antidepressant, anticonvulsant, analgesic and anti-emetic agents.
It will be appreciated that the compounds of formula (I) contain at least four asymmetric carbon atoms, three being in the cyclopropane ring and one being at the xcex1-carbon of the amino acid group. Accordingly, the compounds of the invention may exist in and be isolated in enantiomerically pure form, in racemic form, or in a diastereoisomeric mixture.
The amino acid moiety preferably has the natural amino configuration. Accordingly, preferred compounds according to the invention are those of the formula: 
In the above general formulae, a C1-10 alkyl group includes a C1-4 alkyl group and can be straight or branched chain, such as, for example, methyl, ethyl, propyl, isopropyl, butyl and isobutyl, and is preferably methyl or ethyl. A C2-10 alkenyl group includes, for example, vinyl, prop-2-enyl, but-3-enyl, pent-4-enyl and isopropenyl, and an alkenyl group can contain more than one double bond and, in addition, one or more triple bonds. A preferred alkenyl group is of the formula Rxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)rxe2x80x94 where Rxe2x80x2 is hydrogen or C1-4 alkyl and r is 0, 1 or 2. A C2-10 alkynyl group includes, for example, prop-2-ynyl, but-3-ynyl, pent-4-ynyl and oct-7-ynyl, and is preferably of the formula Rxe2x80x3Cxe2x95x90Cxe2x80x94(CH2)sxe2x80x94 where Rxe2x80x3 is hydrogen or C1-4 alkyl and s is 0, 1 or 2.
Included within the group of compounds of formula I are those compounds in which R1 is C1-10 alkyl; C2-10 alkenyl or C2-10 alkynyl.
Examples of particular values for R1 are:
for a C1-10 alkyl group: methyl, ethyl, propyl and isopropyl;
for a C2-10 alkenyl group: vinyl; prop-2-enyl and isopropenyl;
for a C2-10 alkynyl group: propynyl;
for a phenyl-C2-10 alkyl group: 2-phenylethyl; and
for a phenyl-C2-10 alkenyl group: 2-phenylvinyl.
Preferably R1 is selected from methyl, ethyl, propyl, isopropyl, vinyl, prop-2-enyl, isopropenyl and propynyl.
Especially preferred are compounds in which R1 is methyl or vinyl.
Particularly preferred compounds are:
(2S,1xe2x80x2S,2xe2x80x2S,3xe2x80x2R)-2-(3xe2x80x2-methyl-2xe2x80x2-carboxycyclopropyl)-glycine;
(2S,1xe2x80x2s, 2xe2x80x2S,3xe2x80x2R)-2-[3xe2x80x2-(2xe2x80x3-ethyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2S,1xe2x80x2S,2xe2x80x2S,3xe2x80x2R)-2-[3xe2x80x2-(3xe2x80x3-propyl)-2xe2x80x2-carboxycyclopropyl]glycine;
(2SR,1xe2x80x2SR,2xe2x80x2SR,3xe2x80x2RS)-2-(3xe2x80x2-vinyl-2xe2x80x2-carboxycyclopropyl)-glycine; and
(2S,1xe2x80x2S,2xe2x80x2S,3xe2x80x2R)-2-[3xe2x80x2-(2xe2x80x3-phenylethyl)-2xe2x80x2carboxycyclopropyl]glycine;
and pharmaceutically acceptable salts and esters thereof.
The present invention includes salts of the formula (I) compounds. These salts can exist in conjunction with the acidic or basic portion of the molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary ammonium, alkali metal, or alkaline earth metal salts. Generally, the acid addition salts are prepared by the reaction of an acid with a compound of formula (I). The alkali metal and alkaline earth metal salts are generally prepared by the reaction of the hydroxide form of the desired metal salt with a compound of formula (I).
The salts of the compounds of formula I may be pharmaceutically-acceptable salts. However, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically-acceptable, acid addition salts, or are useful for identification, characterisation or purification.
Acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic, or naphthalene-2-sulphonic acid.
The present invention includes esters of the formula (I) compounds, such esters being for example aliphatic esters such as alkyl esters.
The esters of the compounds of formula I may be pharmaceutically acceptable metabolically labile esters of compounds of formula I. These are ester derivatives of compounds of formula I that are hydrolyzed in vivo to afford said compound of formula I and a pharmaceutically acceptable alcohol. Examples of metabolically labile esters include esters formed with (1-6C) alkanols in which the alkanol moiety may be optionally substituted by a (1-8C) alkoxy group, for example methanol, ethanol, propanol and methoxyethanol. The most preferred esters are alkyl esters derived from C1-4 alkanols, especially methyl and ethyl esters.
The invention also comprises a process for preparing a compound according to formula (I), or a salt or ester thereof, which comprises:
(a) deprotecting a compound of formula 
xe2x80x83in which R2 and R3 each independently represents hydrogen or a carboxyl protecting group, and R4 represents hydrogen or an amine protecting group;
(b) hydrolysing a compound of formula 
xe2x80x83in which R5 represents a hydrogen atom or a carboxyl protecting group, and R6 and R7 each independently represents a hydrogen atom, a C1-4 alkyl group, a phenyl C1-4 alkyl group in which the phenyl group is unsubstituted or substituted by halo, C1-4 alkyl or C1-4 alkoxy, or C3-4 alkenyl; or
(c) hydrolysing a compound of formula 
xe2x80x83in which R1 represents a hydrogen atom or a carboxy protecting group, and R9 represents a hydrogen atom or an amine protecting group;
followed when necessary by recovering a diastereomer or isomer of the compound, or
forming a salt or ester thereof.
The protection of carboxylic acid groups is described in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973, and Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd. Ed., John Wiley and Sons, NY, 1991. Examples of carboxy protecting groups include C1-C6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aryl(C1-C4)alkyl groups such as benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, benzhydryl and trityl; silyl groups such as trimethylsilyl and t-butyldimethylsilyl; and allyl groups such as allyl and 1-(trimethylsilylmethyl)prop-1-en-3-yl.
Examples of amine protecting groups include acyl groups, such as groups of formula R10CO in which R10 represents C1-6 alkyl, C3-10 cycloalkyl, phenyl C1-6 alkyl, phenyl, C1-6 alkoxy, phenyl C1-6 alkoxy, or a C3-10 cycloalkoxy, wherein a phenyl group may be optionally substituted, for example by one or two of halogen, C1-C4 alkyl and C1-C4 alkoxy. Preferred amino protecting groups include t-butoxycarbonyl (Boc) and benzyl.
Examples of particular values for R2, R3, R5 and R8 are hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, benzyl, 4-methoxybenzyl, phenylethyl and phenylpropyl.
Examples of particular values for R4 and R9 include acetyl and tert-butoxycarbonyl.
Examples of particular values for R6 and R7 are hydrogen and benzyl.
The compounds of formula (II) may be deprotected by conventional methods. Thus, an alkyl carboxyl protecting group may be removed by hydrolysis. The hydrolysis may conveniently be performed by heating the compound of formula (II) in the presence of either a base, for example an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, or an alkaline metal hydroxide, such as barium hydroxide or an acid such as hydrochloric acid. The hydrolysis is conveniently performed at a temperature in the range of from 20xc2x0 C to 300xc2x0 C. An aralkyl carboxyl protecting group may conveniently be removed by hydrogenation. The hydrogenation may be effected by reacting the compound of formula (II) with hydrogen in the presence of a Group VIII metal catalyst, for example a palladium catalyst such as palladium on charcoal. Suitable solvents for the reaction include alcohols such as ethanol. The reaction is conveniently performed at a temperature in the range of from 0xc2x0 C. to 100xc2x0 C.
An acyl, amine protecting group is also conveniently removed by hydrolysis, for example as described for the removal of an alkyl carboxyl protecting group. Thus, a tert-butoxycarbonyl, amine protecting group may conveniently be removed in the presence of an acid, for example hydrochloric acid or trifluoroacetic acid. The hydrolysis is performed in the presence of a solvent such as water, ethyl acetate or dichloromethane and at a temperature in the range of from 20xc2x0 C. to 100xc2x0 C.
The compounds of formula III are conveniently hydrolyzed in the presence of a base, for example an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, or an alkaline earth metal hydroxide such as barium hydroxide. Suitable reaction media include water. The temperature is conveniently in the range of from 50xc2x0 C. to 150xc2x0 C.
The compounds of formula IV are conveniently hydrolyzed in the presence of an acid, such as hydrochloric acid or sulfuric acid, or a base, such as an alkali metal hydroxide, for example sodium hydroxide. The hydrolysis is conveniently performed in an aqueous solvent such as water, or in an alkanol such as methanol or ethanol, and at a temperature in the range of from 20xc2x0 C. to 200xc2x0 C.
Compounds of formula (II) may be prepared by a procedure analogous to that described in Ohfune Y., et al., J. Med. Chem., 1996, 39, 407-423. Thus they may be prepared by reacting a compound of formula 
with an oxidising agent. Convenient oxidising agents include Jones Reagent.
Compounds of formula (V) may be prepared by reacting a compound of formula 
with a sulfonic acid, such as camphorsulfonic acid (CSA) and an alkanol, such as methanol.
Compounds of formula (VI) may be prepared by reacting a compound of formula 
with a strong base, such as potassium hexamethyldisilane.
Compounds of formula (VII) may be prepared by reacting a compound of formula 
with acetone dimethyl ketal in the presence of a sulfonic acid, such as camphorsulfonic acid.
Compounds of formula VIII may be prepared by selectively deprotecting a compound of formula 
in which R11 represents a hydroxyl protecting group, such as a tert-butyldimethylsilyl (TBS) group. A convenient reagent for removing a TBS group is camphorsulfonic acid in methanol.
The compounds of formula (IX) may be prepared by reacting a compound of formula 
with a base, such as lithium hydroxide, for example in tetrahydrofuran, followed by introduction of the protecting group R2, for example by treatment with diazomethane (to afford a compound in which R2 is methyl).
Compounds of formula (X) may be prepared by treating a compound of formula 
with an ion exchange resin, such as DOWEX 50Wx8, followed by introduction of the protecting groups R4 and R11, for example by stepwise reaction with tributylsilyl chloride in the presence of imidazole, followed by Boc2O in the presence of triethylamine and 4 dimethylaminopyridine.
Compounds of formula (XI) may be prepared by reacting a compound of formula 
with palladium(II)acetate.
Compounds of formula (XII) may be prepared by diazotizing a compound of formula 
for example by reaction with sodium nitrite.
Compounds of formula (XIII) may be prepared by selectively deprotecting a compound of formula 
in which R12 represents an amine protecting group, such as t-butoxycarbonyl. For example a t-butoxycarbonyl (Boc) group may conveniently be removed by treatment with trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine.
The compounds of formula (XIV) may be prepared by reacting a compound of formula 
with an N-protected glycinate, such as N-hydroxysuccinimide N-(tert-butoxycarbonyl)glycinate, followed by reaction with acetone dimethylketal in the presence of a sulfonic acid such as p-toluenesulfonic acid.
The compounds of formula (XV) may be prepared by reacting a compound of formula 
in which R13 represents an amine protecting group, such as t-butoxycarbonyl, with a triphenylphosphine halide of formula Ph3P+CH2R1 Axe2x88x92, in which Axe2x88x92 represents a halide ion such as bromide, in the presence of a strong base, such as potassium hexamethyldisilane, followed by removal of the amine protecting group, and hydrolysis of the acetonide, for example by reaction with methanolic HCl.
Compounds of formula (II) may also be prepared by reacting a compound of formula 
with a Wittig reagent. For example, the compound of formula (XVII) may be reacted with an alkyl triphenylphosphonium bromide, such as methyl triphenylphosphonium bromide to afford a compound of formula (II) in which R1 represents an alkenyl group, such as vinyl. The resultant product may then, if desired, be converted into another compound of formula (II), for example by catalytic hydrogenation to convert an alkenyl group to an alkyl group.
Compounds of formula (XVII) may be prepared by Swern oxidation of a compound of formula 
The compounds of formula XVIII may be prepared either by hydrolysing a compound of formula XIX 
for example using HCl in aqueous ethanol, followed by protecting the amino group, for example by reaction with Boc2O in tetrahydrofuran or dioxane in the presence of
NaHCO3,
or by hydrolysing a compound of formula XX 
in the presence of a base, for example sodium hydroxide, in an aqueous solution at an elevated temperature, for example about 100xc2x0 C., followed by protecting the carboxylic acid groups, for example using HCl in anhydrous ethanol, and protecting the amino group, for example by reaction with Boc2O in tetrahydrofuran or dioxane in the presence of NaHCO3.
The compounds of formula XIX may be prepared by reacting a compound of formula XXI 
with ammonium chloride and potassium cyanide in the presence of aluminium oxide. A convenient solvent is acetonitrile.
The compounds of formula XX may be prepared by hydrolysing a compound of formula XXI with an alkali metal hydroxide, for example using sodium hydroxide in aqueous ethanol, followed by treatment with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and ammonium carbonate in an aqueous alcohol, such as aqueous ethanol. Conveniently the reaction is performed at a temperature of from 35xc2x0 C. to 150xc2x0 C.
Compounds of formula XXI may be prepared by oxidising a compound of formula XXII 
for example by employing a Swern oxidation.
Compounds of formula XXII may be prepared by reacting a compound of formula 
in which R14 represents a hydrogen atom, a C1-4 alkyl group or a phenyl group, with HCl or camphorsulphonic acid in an alkanol such as ethanol.
Compounds of formula XXIII may be prepared by reacting a compound of formula 
with N2CHCO2R2 in the presence of Rh2(OAc)4. A convenient solvent is pentane.
The compounds of formula (III) may be prepared by reacting a compound of formula 
with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and ammonium carbonate in an aqueous alcohol, such as aqueous ethanol. Conveniently the reaction is performed at a temperature of from 35xc2x0 C. to 150xc2x0 C. If desired, the compounds of formula (III) may then be alkylated, for example using a compound of formula R6Cl or R7Cl. The alkylated compounds are readily separated into their diastereomers.
Compounds of formula (IV) may be prepared by reacting a compound of formula (XXV), in which R8 is as defined for R5, with an alkali metal cyanide, such as lithium, sodium or potassium cyanide, and an ammonium halide, such as ammonium chloride. It has been found advantageous to perform the reaction in the presence of ultrasound. Thus, the ammonium halide and alkali metal cyanide are advantageously mixed with chromatography grade alumina in the presence of a suitable diluent, such as acetonitrile. The mixture is then irradiated with ultrasound, whereafter the compound of formula XXV is added, and the mixture is again irradiated.
The resultant mixture of diastereoisomeric aminonitriles may then be reacted with an acylating agent, such as acetyl chloride in the presence of a suitable base, for example an amine such as diisopropylamine, and in the presence of a suitable solvent such as dichloromethane, to afford a mixture of diastereomeric acylaminonitriles. The desired stereoisomer may conveniently be separated from this mixture, for example by chromatography.
Alternatively, compounds of formula (IV) may be prepared by reacting a compound of formula (XXV) with a chiral 2-arylglycinol, such as (R)-2-phenylglycinol, followed by trimethylsilylcyanide. The reaction is conveniently conducted in the presence of a solvent such as methanol. The product of the reaction is a mixture of diastereomers corresponding with formula (IV) in which R9 represents a 1-aryl-2-hydroxyethyl group. The desired diastereomer may be isolated from the mixture, for example by chromatography, and then reacted with an oxidising agent such as lead tetraacetate to afford a compound of formula (IV).
The compounds of formula (XXV) may be prepared by oxidising a compound of formula 
for example by a Swern oxidation, or by reaction with tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide in the presence of a molecular sieve (4 xc3x85).
The compounds of formula (XXVI) may be prepared by reacting a compound of formula (XXI) with a Wittig reagent of formula Ph3P+CH2R15 is Axe2x88x92, in which Axe2x88x92 represents a halide ion such as bromide and R15 represents a hydrogen atom or an alkyl group, in the presence of a strong base, such as potassium hexamethyldisilane. Convenient solvents include ethers, such as dioxan. The resultant alkenyl compound may be reduced to afford an alkyl compound, for example by catalytic hydrogenation using palladium on charcoal as catalyst.
The compounds of formula (XXV) may alternatively be prepared by reacting a compound of formula (XXVII) 
with an alkali metal hydroxide, such as sodium hydroxide, in an aqueous alcohol solvent, such as aqueous methanol, followed by diazomethane. The process affords a mixture. of a compound of. formula (XXVI) and a compound of formula (XXV), which may then be reacted with a chiral 2-arylglycinol and trimethylsilylcyanide as described hereinabove.
The compounds of formula XXVII may be prepared by reacting a compound of formula 
for example by a Swern oxidation, or by reaction with tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide in the presence of a molecular sieve (4 xc3x85).
The compounds of formula (XXVIII) may be prepared by reacting a compound of formula 
with an alkali metal hydroxide, such as lithium hydroxide, to afford a compound of formula (XXVIII) in which R5 represents hydrogen, followed by followed by introducing a protecting group R5, for example by reaction with diazomethane to produce a compound in which R5 is methyl.
The compounds of formula (XXIX) may be prepared by reacting a compound of formula 
with dirhodium(II)tetrakis[methyl 2-pyrrolidone-5(R)-carboxylate].
The compounds of formula (XXX) may be prepared by reacting a compound of formula 
with a sulfonyl azide such as p-acetamidobenzenesulfonyl azide in the presence of a base, such as triethylamine, followed by reaction with an aqueous alkali metal hydroxide, such as lithium hydroxide.
The compounds of formula (XXXI) may be prepared by reacting a compound of formula 
with diketene in the presence of an alkali metal acetate, such as sodium acetate.
As described hereinabove, the compounds of the invention are useful for the treatment of disorders of the central nervous system.
According to another aspect therefore, the present invention provides a method of treating a patient suffering from or susceptible to a disorder of the central nervous system, which comprises administering an effective amount of a compound of formula I as defined hereinabove, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof.
The particular effective amount or dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may be administered by continuous infusion. A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
A variety of physiological functions have been shown to be subject to influence by excessive or inappropriate stimulation of excitatory amino acid transmission. The formula I compounds of the present invention are believed to have the ability to treat a variety of neurological disorders in patients associated with this condition, including acute neurological disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, and. hypoglycemic neuronal damage. The formula I compounds are believed to have the ability to treat a variety of chronic neurological disorders, such as Alzheimer""s disease, Huntington""s Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, ocular damage and retinopathy, cognitive disorders, and idiopathic and drug-induced Parkinson""s. The present invention also provides methods for treating these disorders which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable. salt thereof.
The formula I compounds of the present invention are also believed to have the ability to treat a variety of other neurological. disorders in patients that are associated with glutamate dysfunction, including muscular spasms, convulsions, migraine headaches, urinary incontinence, psychosis, (such as schizophrenia), drug tolerance and withdrawal (such as nicotine, opiates and benzodiazepines) , anxiety and related disorders, emesis, brain edema, chronic pain, and tardive dyskinesia. The formula I compounds are also useful as antidepressant and analgesic agents. Therefore, the present invention also provides methods for treating these disorders which comprise administering to a patient in need thereof an effective amount of the compound of formula I, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof.
The term xe2x80x9ctreatingxe2x80x9d for purposes of the present invention, includes prophylaxis, amelioration or elimination of a named condition once the condition has been established.
The term xe2x80x9cpatientxe2x80x9d for purposes of the present invention is defined as any warm blooded animal such as, but not limited to, a mouse, guinea pig, dog, horse, or human. Preferably, the patient is human.
According to another aspect, the present invention provides a compound of formula I as defined hereinabove, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
According to yet another aspect, the present invention provides the use of a compound of formula I as defined hereinabove, or a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder of the central nervous system.
The ability of compounds to modulate metabotropic glutamate receptor function may be demonstrated by examining their ability to influence either cAMP production (mGluR 2, 3, 4, 6, 7 or 8) or phosphoinositide hydrolysis (mGluR 1 or 5) in cells expressing these individual human metabotropic glutamate receptor (mGluR) subtypes. (D. D. Schoepp, et al., Neuropharmacol., 1996, 35, 1661-1672 and 1997, 36, 111).
In these tests the compound of Example 1 of the present application was found to reverse [3 H] LY341495 binding with a Ki of 100.2 nM at mGluR2. In comparison, (2S,1xe2x80x2S,2xe2x80x2S,3xe2x80x2S)-2xe2x80x2-carboxy-3xe2x80x2methylcyclopropylglycine, disclosed in EP-A-0870760 was found to reverse [3 H] LY341495 binding with a Ki of 2645 nM at mGluR2. (LY341495 is described in Ornstein et al., J. Med. Chem., 1998, 41, 346-357 and J. Med. Chem., 1998, 41, 358 to 378).
The compounds of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical formulation comprising a compound of formula I, a pharmaceutically acceptable metabolically labile ester thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically-acceptable carrier, diluent, or excipient. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to a physically. discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
The following Examples illustrate the invention. In the Examples, the term xe2x80x9cGarner""s aldehydexe2x80x9d signifies 1,1-dimethylethyl (S) or (R)-4-formyl-2,2-dimethyl-3-oxazolidine carboxylate, Ph3PEtBr signifies (ethyl)triphenylphosphonium bromide, KHDMS and LiHDMS signify potassium and lithium hexamethyldisilazane. respectively, Et2O signifies diethylether, AcOEt signifies ethyl acetate, MeOH signifies methanol, Boc signifies t-butoxycarbonyl, Et3N signifies triethylamine, THF signifies tetrahydrofuran, TMSOTf signifies trimethylsilyl trifluoromethanesulfonate, Pd(OAc)2 signifies palladium acetate, NMO signifies N-methylmorpholine-N-oxide, TPAP signifies tetrapropylammonium perruthenate, TMSCN signifies trimethylsilylcyanide, Rh2(5R-MEPY)4 signifies dirhodium(II)tetrakis[methyl 2-pyrrolidone-5(R)-carboxylate], DMF signifies dimethylformamide, DMAP signifies 4-dimethylaminopyridine, Jones Reagent signifies a solution of 1.0 g of Na2Cr2O7.2H2O and 1.34 g of sulfuric acid in H2O (total volume 5 ml), DBU signifies 1,8-diazabicyclo[5.4.0]undec-7-ene and DME signifies ethylene glycol dimethyl ether.